Alzheimer's disease (AD) and senile demetia of the Alzheimer's type (SDAT) are the most common causes of dementia in middle and old age. Patients with AD/SDAT show reduced cholinergic presynaptic markers in the cerebral cortex, but the location of the cholinergic neurons at risk is unknown. Recent evidence suggests that much of the cholinergic cortical innervation arises from the neurons in the nucleus basalis of Meynert (nbM). We have hypothesized and have provided preliminary evidence that loss of nbM neurons is a patological correlate of the deficiency of cholinergic markers in cortex. To test this hypothesis, we have begun to prepare anatomical/histochemical and neurochemical (choline acetyltransferase [CAT]) maps of the basal forebrain in normal monkeys and humans. To assess the changes in nbM cells and CAT activity during normal aging, a similar approach will be used in aged monkeys (15-31 years) and humans (sixth to ninth decades). To determine the effects of destruction of nbM cells on CAT activity, ibotenic acid, an excitotoxin knwon to destroy neurons in the basal forebrain, will be stereotactically microinjected into electrophysiologically-mapped nbM of monkeys. Our hypothesis predicts that ablation of the nbM will result in a reduciton in CAT activity in both the nbM and in the cortex; bilaterally-lesioned monkeys may be a useful model for behavioral, pharmacological, and therapeutic studies of cortical cholinergic abnormalities. Finally, to assess the role of basal forebrain cholinergic systems in human dementia, neuropathological/neurochemical approaches will be used to evaluate the nbM and cortex in several types of human dementia in which cholinergic abnormalities have been suggested, e.g., AD/SDAT, Parkinson's disease (with dementia), and Down's syndrome (with late onset demetia). Identification of a transmitter-specific neuronal pathology associated with cognitive disturbances is an important step in understanding the functional abnormalities occurring in dementia and may lead to more specific treatments of this disabling group of neurological disorders.